Local anaesthetic to reduce injection pain in patients who are prescribed intramuscular benzathine penicillin G: a systematic review and meta-analysis

Summary Background Three to 4-weekly intramuscular injections of benzathine penicillin G (BPG) for a prolonged period (e.g., 10 years, until age 40 years, or lifelong) are recommended for preventing group A streptococcal infections that cause recurrent acute rheumatic fever (ARF) and potential progression to rheumatic heart disease (RHD). The duration of treatment, frequency and local pain associated with BPG injections may lead to reduced compliance. Shorter courses of BPG are recommended for the treatment of syphilis and Streptococcal infections. We aimed to assess the effects of local anaesthesia in reducing injection pain in patients who are being treated with BPG. Methods In this systematic review and meta-analysis, we searched the Cochrane Central Register of Controlled Trials, MEDLINE, EMBASE, Conference Proceedings Citation Index-Science and LILACS from database inception up to May 4, 2024, and performed additional searches for grey literature. Randomised controlled trials comparing BPG vs. BPG administered alongside local anaesthetics were included. Randomized controlled trials using BPG, irrespectively of indication, and testing any local anaesthetic agent for pain alleviation were considered eligible. We applied GRADE to assess the quality of evidence. Summary data were extracted from included trials. The primary outcome was injection pain, assessed through mean differences. A random-effects model was utilized to account for study heterogeneity. This study is registered with PROSPERO, CRD42022342437. Findings Database searches identified a total of 3958 records, and 3 additional records were retrieved from grey literature searches. After removal of duplicates, screening of abstracts and full-text review, eight trials were included, combining a total of 489 patients (151 patients with RHD). Immediate pain level, as reported by patients, was of high intensity in most studies. Low intensity pain was still reported at 24 h. Administration of lidocaine mixed with BPG was associated with a significant reduction in immediate post-injection pain (mean difference −3.84, 95% confidence interval −6.19 to −1.48, P = 0.0001; 4 studies; I2 = 98%; GRADE: moderate quality), pain at 5 min (mean difference −2.85, 95% CI confidence interval −3.78 to −1.92, P < 0.0001; 1 study; GRADE: moderate quality), and pain at 20 min (mean difference −1.85, 95% confidence interval −2.61 to −1.09, P < 0.0001; 1 study; GRADE: moderate quality) on a 1 to 10 scale. One study assessed lidocaine cream applied to the skin prior to BPG injection and showed no significant reduction in injection pain (mean difference = −0.54, 95% CI confidence interval −1.17 to 0.09, P = 0.13; 1 study; GRADE: low quality). Mepivacaine mixed with BPG in patients with syphilis showed a significant reduction of immediate post-injection pain (mean difference −2.19, 95% CI confidence interval −2.49 to −1.89, P < 0.0001; 1 study; GRADE: moderate quality). Two studies assessed procaine mixed with BPG and reported: lower immediate pain levels or pain assessed at 1 h (mean difference and 95% CI confidence intervals not provided, P = 0.001 and P = 0.008, respectively; 1 study; GRADE: low quality), or less immediate pain and pain at 24 h on the buttock injected with procaine mixed with BPG (mean difference and 95% CI confidence intervals not provided, P < 0.001 for both; 1 study; Grade: low quality). No severe adverse reactions were reported. Interpretation In patients receiving intramuscular BPG injections, moderate quality quantitative evidence suggests that BPG injections diluted with lidocaine or mepivacaine may improve post-injection pain scores compared to BPG injections diluted with sterile water. Procaine may also have a benefit, but quality of evidence was lower. Most studies included small patient samples and assessed pain levels at different timepoints. Due to insufficient data we were not able to assess the impact of injection volume, and local anaesthetics’ dose on pain intensity and duration of pain relief. Funding 10.13039/100004423WHO.


BPG formulations
-Lyophilised powder packaged in vials, which needs to be mixed with sterile diluent at point of care.
-Viscous liquid in pre-filled syringes that need to be stored on a refrigerator (temperature 2 to 8 o C); Bicillin® L-A (Pfizer) is available in three dosages: 0.6MU (1.17mL), 1.2MU (2.3mL) and 2.4MU (4.6mL) Note: During a recent period of shortage of Bicillin® L-A in Australia, guidance has been issued by Menzies school of health research, National Aboriginal Community Controlled Health Organization, and the Northern Territory Government, on the preparation of BPG 1.2MU powder for suspension: -  Not an RCT; controlled study assessing patients' experience following 3 monthly im BPG injections: first diluted in water 2nd and 3 rd diluted in lidocaine.

Basak et al. 2021
Wrong intervention; RCT assessing impact of virtual reality and distraction cards on pain associated with im BPG injection.

Cooper et al. 2023
Qualitative study describing experiences of young RHD patients receiving subcutaneous lidocaine 2% followed by subcutaneous BPG.

Derya et al. 2015
Wrong intervention; RCT assessing impact of manual pressure before im BPG injection on pain.

Douglas et al. 1971
Wrong population: the control group was treated with crystalline penicillin 500,000U every 6h for 5 days (short duration of action form of Penicillin G); study not assessing pain.

Enkel et al. 2023
Qualitative study describing experiences of RHD receiving diierent subcutaneous doses of BPG

Farhadi et al. 2011
Wrong intervention; RCT assessing impact of cold/ice cubes on pain associated with im BPG injection.

Feamley et al. 2020
Not an RCT; Wrong intervention: comparison of single 8mL versus double injection of 4mL im BPG in patients with Syphilis (treatment arm chosen by patients).

Hla et al. 2024
Review paper on subcutaneous BPG for Syphilis.

Huck et al. 2015
Qualitative study; Assessment of factors influencing adherence to secondary prophylaxis.

Janier et al. 2012
Not an RCT; Wrong intervention: comparison of single versus multiple im BPG doses Jakhwal et al. 2018 Wrong intervention; Ongoing RCT assessing impact of Helfer Skin Tap on pain associated with im BPG injection.

Kado et al. 2020
Wrong intervention; RCT comparing pharmacokinetic profile and tolerability of subcutaneous versus im BPG Kado et al. 2023 Wrong intervention; RCT assessing 3 doses of subcutaneous BPG and impact on pain and concentration over time.High-dose subcutaneous BPG may be suitable for up to 3 months dosing intervals for secondary prophylaxis of RHD.

Madeira et al. 2016
Editorial Mitchell et al. 2018 Qualitative study; assessing patients and clinicians experiences on BPG intramuscular pain.

Musoke et al. 2014
Qualitative study; Assessment of factors influencing adherence to secondary prophylaxis.

Oliveira et al. 2015
Wrong intervention; RCT assessing impact of alternative location for BPG injection on pain.

Russel et al. 2014
Not an RCT; Study assessing impact of choice of lidocaine, Buzzy, both or nothing on pain among patients receiving im BPG.

Saxena et al. 2015
Not an RCT: Observational study assessing adherence in a registry/tertiary center.

Sivri Bilgen et al. 2019
Wrong intervention; RCT assessing the eiect of Buzzy or ShotBlocker on perceived pain in im injections.

Thomas et al. 2019
Wrong intervention; RCT assessing impact of needle temperature on pain among patients receiving penicillin injections

Tuğrul et al. 2014
Wrong intervention; RCT assessing impact of site and speed of injection on pain associated with im BPG.

Wyber et al. 2016
Qualitative study; consultation with global experts in RHD on the characteristics of BPG formulations which could be changed to improve adherence with secondary prophylaxis.

Ongoing study
Pareeda T. A randomized controlled study of comparison of pain score after intramuscular injection of Benzathine penicillin in female patients with syphilis among cold compression before injection, 1% Lidocaine solution and combination between cold compression before injection and 1% Lidocaine solution.

Table S -1: Table of excluded studies Study name Reason for exclusion Adnan et al. 2013
World Health Organization International Clinical Trials Registry Platform.Date of Registration: 3 rd August 2020.TCTR20200803003 Available at: https://trialsearch.who.int/Trial2.aspx?TrialID=TCTR20200803003 , accessed 10 th May 2024 Mariano AG.Pain Alleviation of Intramuscular Injection with Lidocaine versus Distilled Water in the Diluent of Benzathine Benzylpenicillin among Children with Rheumatic Fever and Rehumatic Heart Disease at MCU -FDTMF Hospital: A Prospective, Randomised Controlled Trial, Crossover Study.Master Thesis.2023.Abstract available at: https://www.herdin.ph/index.php?view=research&cid=81593 , accessed 4 th May 2024 Tabin C, Salvador ME, Manangan MR.Comparison of Pain Scale Using Lidocaine as a Diluent versus Lidocaine plus Coughing technique during Benzathine Penicillin G administration in Pediatric patients with Rheumatic Fever and Rheumatic Heart Disease.World Congress on Rheumatic Heart Disease 2023, 2-4 November 2023, Abu Dhabi;

Table S -
3. Sub-analyses and Sensitivity analyses Intramuscular Lidocaine versus Placebo